Tetrahydroisoquinolinalkanol esters of cycloaliphatic acids and derivatives thereof



Patented June 22, 1954 UNITED STATES PATENT OFFICETETRAHYDROISOQUINOLINALKANOL ES- TERS OF CYCLOALIPHATIC ACIDS ANDDERIVATIVES THEREOF John W. Cusic, Skokie, 111., assignor to G. D.

nois

Searle & 00., Chicago, 111., a corporation of Illi- No Drawing.Application October 29, 1951, Serial No. 253,750

8 Claims.

The present invention relates to a new group of heterocyclic organiccompounds and, more particularly, to derivatives of1,2,3,4-tetrahydroisoquinoline and their salts, which are substituted inthe 2-position by a lower cycloalkanoylalkyl radical. Of specialinterest are the 1,2,3,4-tetrahydroisoquinoline derivatives whichcontain in the 2-position a cycloalkanoylalkyl radical of the typesubstituted isoquinolines containing nuclear substituents such as loweralkyl, lower alkoxy, lower alkylenedioxy, lower aralkyl, lower aryl, andlower aryloxy radicals.

The organic bases described herein form salts with a variety ofinorganic and strong organic acids, including sulfuric, phosphoric,hydrochloric, hydrobromic, hydriodic, sulfamic, citric, lactic, maleic,malic, succinic, tartaric, cinnamic, acetic, benzoic, gluconic, oxalic,ascorbic, and related acids. They also form quaternary ammonium saltswith a variety of organic esters of sulfuric, hydrohalic and aromaticsulfonic acids. Among such esters are methyl chloride, bromide andiodide; ethyl chloride, propyl chloride, butyl bromide, isobutylchloride, benzyl chloride, phenethyl chloride, naphthylmethyl chloride,dimethyl sulfate, methyl benzenesulfonate, ethyl toluenesulfonate,ethylene chlorohydrin, propylene chlorohydrin, allyl chloride, methallylbromide and crotyl bromide.

The esters which constitute the present invention are valuable asintermediates in organic synthesis. Their salts are of value asmedicinal agents because of their effect on cardiovascular, renal, andnervous functions. They are of value as active ingredients inparasiticidal compositions of matter.

One of the most convenient ways of preparing the compounds of thisinvention is represented schematically as follows:

OyC,.H2-C O OCmH2m X being halogen and all other symbols being definedas hereinabove.

Another method consists in the direct introduction of the side-chain inthe 2-position by heating the 1,2,3, l-tetrahydroisoquinoline with ahalide of the type all symbols being defined as hereinabove.

My invention is disclosed in further detail by the following exampleswhich are set forth for the purpose of illustrating this invention, butare in no way to be construed as limiting it in spirit or in scope. Itwill be apparent to those skilled in the art of organic synthesis thatmany conventional modifications in methods, conditions and materials canbe adopted without departing therefrom. In each of these examplesquantities of materials are expressed as parts by weight, temperaturesas degrees centigrade C.), and pressures during vacuum distillation asmillimeters (mm.) of mercury.

EXAMPLE 1 1,2,3,4-tetrahydroisoquinoline-Z-ethanolcyclopentanecarbomylate hydrochloride On mixing of 132 parts ofcyclopentanecarbonyl chloride and 177 parts of1,2,3,4-tetrahydroisoquinoline-Z-ethanol in 2600 parts of benzene, anoily precipitate separates which solidifies after heating at refluxtemperature for one hour. After cooling, the reaction mixture is treatedwith ether and the solid precipitate collected on a filter andrecrystallized from isopropanol, using charcoal as a decolorizing agent.The solid hydrochloride of 123,4 tetrahydroisoquinoline-2-ethanolcyclopentanecarboxylate thus obtained melts at about 171-172" C. It hasthe structural formula EXAMPLE 21,2,3,4-tetrahydroisoquinoline-2-ethanol cycloheranecarboacylatehydrochloride EXAMPLE 3 1,2,3,4-ietrahydroisoquinoline-2-ethaholcyclohemneacetaie hydrochloride 177 parts of1,2,3,4-tetrahydroisoquinoline-2- ethanol are mixed with 160 parts ofcyclohexaneacetyl chloride in 2500 parts of benzene. There occurs animmediate formation of a solid precipitate. reflux temperature for onehour, after which The reaction is completed by heating at hours. Aftercooling the solid precipitate is collected on a filter andrecrystallized from isopropanol. The hydrochloride of1,2,3,4-tetrahydroisoquinoline 2 ethanol [3 cyclohexanepropionate meltsat about 20620'7 C. and has the structural formula EXAMPLE 51,2,3,4-tetrahydroisoquinoZine-2-ethanol v-cyclohexanebutyratehydrochloride A mixture of 188 parts of 'y-cyclohexanebutyryl chlorideand 1'77 parts of l,2,3,4-tetrahydroisoquinoline-2-ethanol in 2500 partsof benzene is heated at reflux temperature for 2 hours, cooled andfiltered. The hydrochloride of 1,2,3,4-tetrahydroisoquinoline 2 ethanol7 cyclohexanebutyrate thus collected on the filter is recrystallizedfrom isopropanol. It melts at about 196-197 C. and has the structuralformula EXAMPLE 6 1,2,3,4-tetrahydroisoquinoline-Z-eihcmolB-cyclohexanevalerate hydrochloride A mixture of 202 parts offi-cyclohexanevaleryl chloride and 177 parts of1,2,3A-tetrahydroisoquinoline-Z-ethanol in 2500 parts of benzene isheated at reflux temperature for one hour. After cooling the solidprecipitate is collected on a filter and recrystallized fromisopropanol. The hydrochloride of 1,2,3,4-tetrahydroisoquinoline-2ethanol a-cyclohexanevalerate thus obtained melts at about 170-17 1 C.and has the structural formula the precipitate is collected on a filterand recrystallized from dilute isopropanol. The hydrochloride of123,4-tetrahydroisoquinoline-2- ethanol cyclohexaneacetate thus obtainedmelts at about 211-212 C. and has the structural formula EXAMPLE 41,2,3,4-ietrahydroisoquinoline-Zethanol B-cy clohemanepropionatehydrochloride A mixture of 1'74 parts of ,B-cyclohexane propionylchloride and 177 parts of 1,2,3,4-tetrahydroisoquinoline-2-ethanol in2500 parts of benzene is heated at reflux temperature for two EXAMPLE '71,2,3,4-teirahyaroisoquinoline-2-ethcmol ill-cyclohezcaneca'proatehydrochloride A mixture of 216 parts of w-cyclohexanecaproyl chlorideand 177 parts of 1,2,3A-tetrahydroisoquinoline-Z-ethanol in 2500 partsof benzene is heated at reflux temperature for one hour. After coolingthe solid precipitate is collected on a filter and recrystallized fromisopropanol. The hydrochloride of 1,2,3,4-tetrahydroisoquinoline-2-ethanol w-cyclohexanecaproate melts at about 167-168" C. and has thestructural formula l EXAMPLE 8 06,04 Dimethyl 1,2,3;4-tetrahydroisoquinoline- Z-methanol dihydro-u-fencholenate Amixture-M188 parts of dihydro-u-fencholenyl chloride and '160 parts -ofraw-diHlEthYll,2,3,4= tetrahydroisoquinoline 2 methanol in 3000 partsofbenzene is heated at reflux temperature for five hours and thenconcentrated and chilled. The precipitated hydrochloride is collected onafilter, dissolved'in'water, washed with ether, treated with an excessof dilute sodium hydroxide and extracted with ether. The ether extractis dried over anhydrous calcium sulfate, filtered and evaporated'toyield the cad-dimethyl l,2;3;4 tetrahydroisoquinoli'ne 2- methanoldihydro-u-fencholenate as a yellowish, high boiling oil. Ithas'the'Structural formula 235 parts of r the s-bromobutyl ester ofcyclopropaneacetic acid are added to a toluene solution of 440 parts ofanhalonine and heated with stirring at reflux temperature for 24 hours.After cooling and treatment with ether, the reaction mixture is filteredand the filtrate is extracted with hydrochloric acid. The acidic extractis washed with ether, rendered alkaline, and extracted with ether. Thisether extract is dried over anhydrous potassium carbonate, stirred withdecolorizing charcoal, filtered and evaporated to yield a clear, highboiling, amber oil. The 6- anhalonine-2-butanol cyclopropaneacetate thusobtained has the structural formula EXAMPLE 10 1 henyz 3 methyl 1,2,3,4tetrahydroism quinoZine-Z-ethanol cyclobutcmeacetate A mixture of 265parts of cyclobutaneacetyl chloride and 532 parts of 1-phenyl-3-methyl-1,2,3,4-tetrahydroisoquinoline-Z-ethanol in 4000 parts of toluene isheated at reflux temperature for 6 hours and then concentrated andchilled. The precipitate is collected on a filter, dissolved in water,washed with ether, rendered alkaline by addition of ammonium hydroxideand extracted with ether. The resulting ether extract is dried overanhydrous calcium sulfate, stirred with decolorizing charcoal, filteredand evaporated to yield the l-phenyl-B-methyl-1,23,4-tetrahydroisoquinoline 2 ethanol cyclobutaneacetate as a clear, highboiling, orange oil which has the structural formula '6 'EXAMPLE :11

1,2,3,4 -tetrahydroisoquinoline 2 ethanol ncaproate Upon mixing ofl-35-partsof n-caproyl chloride and l'l'lparts ofl,2,3,4-tetrahydroisoquinoline-2- ethanol in 1600=parts-of butanone,there'occurs formation of alsolid precipitate. The reaction is completedby heating-at-refiux temperature for two hours after=which ethanol isadded to destroy any unreactedacid chloride. Themixture is cooled andthe hydrochloride of 1,2,3,4-tetrahydroisoquinoline-2-ethanol n-caproatecollected on a filter and recrystallized from isopropanol. It melts atabout'-l'7-6l77C.

" EXAMPLE 12 1,2,3,4 tetrahydroisoqmnoline 2 ethanol nheptoate On mixingof 250 parts of 'n-heptoyl chloride and 350 parts of1,2,3,4-tetrahydroisoquinoline- Z-ethanol in 2400 parts of butanone,there is formation of a heavy solid precipitate. After refluxing for twohours the mixture is treated with ethanol, and the hydrochloride ofl,2,3,4-tetrahydroisoquinoline-Z-ethanol n-heptoate collected on afilter. Recrystallized from isopropanol using charcoal as a clarifyingagent, it melts at about 174-175" C.

I claim:

1. A member of the class consisting of the esters of the structuralformula and salts thereof, wherein Cy is a lower cycloalkyl radicalcontaining 3 to 6 nuclear carbon atoms inclusive, m is a whole numberbetween 1 and 6 inclusive, n is a whole number between 0 and 6inclusive, and Q is a member of the class consisting of the2-(1,2,3,4-tetrahydro)isoquinolyl radical and 2-(l,2,3,4-tetrahydro)isoquinolyl radicals nuclearly substituted by a member of the classconsisting of lower alkyl, lower alkoxy, methylenedioxy and phenylradicals.

2. A 1,2,3,4 tetrahydroisoquinoline 2 alkanol cycloalkanecarboxylate ofthe structural formula wherein Cy is a lower cycloalkyl radicalcontaining 3 to 6 nuclear carbon atoms inclusive, and m is a wholenumber between 1 and 6 inclusive.

3. l,2,3,4-tetrahydroisoquinoline-2-ethanol cyclopentanecarboxylate.

l. 1,2,3,-tetrahydroisoquinoline-2-ethanol cyclohexanecarboxylate.

5. A 12,3,4 tetrahydroisoquinoline 2 alkanol cycloalkaneacetate of thestructural formula wherein Cy is a lower cycloalkyl radical containing 3to 6 nuclear carbon atoms inclusive, and m is a Whole number between 1and 6 inclusive.

6. A 1,2,3,4 tetrahydroisoquinoline 2 alkanol cycloalkanepropionate ofthe structural formula wherein Cy is a lower cycloalkyl radicalcontaining 3 to 6 nuclear carbon atoms inclusive, and m is a wholenumber between 1 and 6 inclusive.

7. An alkyl 1,2,3,4 tetrahydroisoquinoline- 2-alkanol ester of thestructural formula Cy-G "Ha -C O 0 CmH2m- N (lower alkyl) (lower alkyl)wherein Cy is a lower cycloalkyl radical containing 3 to 6 carbon atomsinclusive and m is a whole number between 1 and 6 inclusive.

No references cited.

1. A MEMBER OF THE CLASS CONSISTING OF THE ESTERS OF THE STRUCTURALFORMULA